This proposal advances the novel paradigm that cancer metastasis, the ultimate cause of death from this disease, may crucially depend on inborn genetic susceptibility factors. Stated otherwise: certain individuals who develop cancer may have good outcomes because they were born inherently resistant to cancer's spread; whereas, other individuals who succumb to cancer may do so due to having an inborn susceptibility to cancer's metastatic spread. We will test this new paradigm in colon cancer, the second leading cause of cancer deaths in the United States, with 150,000 new cases annually, of whom one-third, or 50,000, die because of developing cancer metastasis. We advance this new paradigm because studies from our laboratory show that the existing paradigm, that cancers progress by the cancer cell's multi-step accumulation of increasing numbers of genetic alterations, manifestly fails to explain the final lethal step of colon cancer's metastasizing to distant organ sites. Specifically, our studies sequencing the complete cancer genomes of metastatic and primary colon cancers unexpectedly, but clearly, show that no new mutations are required to generate a colon cancer metastases from a preceding primary colon cancer tumor. These findings directly challenge the paradigm that has dominated cancer genetics for over two-decades. If new gene mutations do not cause cancer metastasis, what then accounts for the difference between the one-third of colon cancers that metastasize and kill, versus the two-thirds that do not? We posit that inborn genetic susceptibility factors that would be common in the population are the major missing factor accounting for difference between persons in whom cancers spread versus those in whom it does not. By analogy, this model extends to cancer metastasis the finding that host genetic resistance factors can be key determinants of survival from potentially lethal infectious challenges. Specifically, this application will identify genetic markers of metastasis susceptibility by using the technique of a whole genome association study to compare the frequency of over 1,000,000 genetic variants between individuals whose colon cancers never metastasized (non-metastatic cases), versus individuals whose colon cancers were metastatic at the time of diagnosis (early-metastatic cases), and versus individuals whose colon cancers relapsed and metastasized following initial complete surgical resections (late-metastatic cases). From these genetic markers of colon cancer metastasis susceptibility we will elucidate the underlying metastasis susceptibility genes, identify the causative metastasis susceptibility variants present in these genes among different ethnic groups, determine if these variants or genes also impart susceptibility to metastasis in other common solid tumors, and determine the biologic pathways by which these susceptibility alleles promote cancer metastasis. Establishing this new paradigm for how cancers spread and kill will yield novel gene targets for cancer prognosis, cancer management, and for development of new anti-cancer therapeutics.